tbuckley/cabot-search huggingface dataset:
Abstract A39: Role of LARP1 in the leukemogenesis of Acute Myeloid Leukemia
Authors: Dominik A Nahotko, Aneta H Baran, Mariafausta Fischietti, Elspeth M Beauchamp, Leonidas C Platanias
Journal: Blood Cancer Discovery (2023)

Abstract Mammalian target of rapamycin (mTOR) is a strong driver of tumorigenesis in multiple types of tumors, however targeting mTOR for cancer therapy has yielded only limited success. This may be explained in part by signaling redundancy with other pathways, such as CDK9 mTOR-Like (CTORC) complexes, recently described by our group. One of the binders common to mTORC1 and CTORC2 is La related protein 1 (LARP1). LARP1 influences ribosome biogenesis by regulating translation of 5'terminal oligopyrimidine tract (5’ TOP) containing mRNAs, which often encode ribosomal proteins and translation factors. Here, we validate LARP1 as common target of mTORC1 and CTORC2 as well as investigate its influence on leukemogenesis. To explore LARP1’s role in leukemogenesis we utilized CRISPR/CAS9 technology to create OCI-AML5 and U937 LARP1 knockout (KO) cells. Loss of LARP1 expression significantly diminished proliferation potential of AML cell lines both in vitro as well as in vivo when implanted into the flank of athymic nude mice as xenografts. Additionally, primary CD34+ leukemia cells were transfected with LARP1 targeting or scrambled siRNA and leukemic progenitor growth was assessed in methocellulose colony formation assays. We observed suppression of leukemic progenitors colony forming ability in LARP1 siRNA transfected cells, compared to the Ctrl siRNA transfected cells. We also determined enhanced sensitivity of Larp1 KO cell lines to standard chemotherapy agents such Azacitidine, Cytarabine and Venetoclax. We employed polysome profiling to compare global translation levels between Larp1 KO and control U937 cells. Our polysomal profiling results show that KO of LARP1 in U937 cells reduces global translation and ribosome biogenesis as expected as we observed a suppression of both monosomal and polysomal peaks. In summary, Larp1 is important for leukemogenesis and influences their response to treatment with currently used chemotherapy agents. These observations together suggest that LARP1 is a promising target for development of novel antileukemia approaches. Citation Format: Dominik A Nahotko, Aneta H Baran, Mariafausta Fischietti, Elspeth M Beauchamp, Leonidas C Platanias. Role of LARP1 in the leukemogenesis of Acute Myeloid Leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A39.
Highlighted research articles
Journal: Blood Cancer Discovery (2023)

In This Issue| May 01 2023 Highlighted research articles Author & Article Information Online ISSN: 2643-3249 Print ISSN: 2643-3230 ©2023 American Association for Cancer Research2023American Association for Cancer Research Blood Cancer Discov (2023) 4 (3): 171. https://doi.org/10.1158/2643-3230.BCD-4-3-ITI Related Content A commentary has been published: METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL A commentary has been published: Molecular Evolution of Classic Hodgkin Lymphoma Revealed Through Whole-Genome Sequencing of Hodgkin and Reed Sternberg Cells A commentary has been published: In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record May 1 2023 Citation Highlighted research articles. Blood Cancer Discov 1 May 2023; 4 (3): 171. https://doi.org/10.1158/2643-3230.BCD-4-3-ITI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Leukemic stem cell (LSC)–targeted therapies remain a significant unmet need in acute myeloid leukemia (AML). Vujovic, de Rooij et al. used an LSC-focused in vivo CRISPR screen to unveil widespread RNA-binding protein (RBP) dependencies in LSCs including top hit ELAVL1. Genetic and pharmacological inhibition of ELAVL1 significantly impaired leukemic propagation and LSC function while relatively sparing hematopoietic stem cells. Integrative multi-omics analyses revealed posttranscriptional enforcement of LSC-supportive mitochondrial metabolism underpinning ELAVL1 function. This study uncovers novel RBP dependencies unique to LSCs and demonstrates ELAVL1 to be an LSC-specific vulnerability with clinical relevance. See article, p. 180. In classic Hodgkin lymphoma (cHL), malignant cells—called Reed Sternberg (HRS) cells—make up only a minority of the tumor. Thus, cell purification is crucial to study cHL genome alterations. Guilino-Roth et al. presented a comprehensive landscape of mutations, copy number, and structural variants of sorted HRS cells and matched normal tissue in cHL obtained... You do not currently have access to this content.
Abstract IA11: Targeting IDH-mutant myeloid leukemia by disabling metabolic dependencies
Authors: Jian Xu
Journal: Blood Cancer Discovery (2023)

Abstract Somatic mutations in catalytic arginine residues of IDH1 and IDH2 contribute to the pathogenesis of acute myeloid leukemia (AML) through the production of the oncometabolite (R)-2-hydroxyglutarate (R-2-HG). Accumulating R-2HG causes epigenetic alterations by impairing αKG-dependent dioxygenases. Allosteric inhibitors of mutant IDH suppress R-2HG production and induce differentiation of leukemic blasts. These findings provide the basis of two targeted therapies for AML (ivosidenib and enasidenib), establishing the first example of personalized therapy based on cancer metabolism. However, the low response rate and the development of resistance to IDHmut inhibitors are major clinical challenges. Moreover, therapy resistance to IDH inhibition can occur through multiple mechanisms, including the selection of R-2HG-restoring second-site mutations or other sub-clonal mutations. These findings underscore the importance of developing more effective approaches for the treatment of IDH-mutant MDS and AML patients. Here we developed a panel of isogenic myeloid leukemia cell lines containing the most common IDH1 or IDH2 oncogenic mutations by CRISPR base editing. By saturation mutagenesis of IDH single-amino acid variants, we identified a repertoire of IDH second-site mutations responsible for therapy resistance through disabling uncompetitive enzyme inhibition. Recurrent mutations at NADPH binding sites within IDH heterodimers act in cis or trans to prevent the formation of stable enzyme-inhibitor complexes, restore R-2HG production in the presence of inhibitors, and drive therapy resistance in IDH-mutant AML cells and patients. Moreover, by transcriptomic and epigenomic profiling of base-edited isogenic cells, we identified a new regulatory axis involving the CD44-mediated rewiring of intracellular metabolism, which is required for mutant IDH-catalyzed R-2-HG production. More importantly, primary and resistant IDH-mutant leukemia cells are sensitive to combined IDH inhibition and genetic or pharmacologic inactivation of CD44 in vitro and in vivo. Taken together, our findings uncover a cell adhesion molecule-mediated metabolic signaling pathway as a new targetable dependency of IDH-mutant leukemia cells, with therapeutic implications for more effective treatment of primary and resistant IDH-mutant myeloid malignancies. Citation Format: Jian Xu. Targeting IDH-mutant myeloid leukemia by disabling metabolic dependencies [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr IA11.
Abstract A32: Exemestane inhibits survival and cell cycle regulators and retards AML cell proliferation
Authors: Mei-chih Chen, Pang-Ting Cheng, Yu-Chiao Cheng, Ho Lin, Chieh-Lin Jerry Teng
Journal: Blood Cancer Discovery (2023)

Abstract Acute myeloid leukemia (AML) is the most common type of leukemia with poor prognosis. Although estrogen plays important roles in female cancers, the recent reports indicate that estrogen and its receptors also attribute to the development of non-gender cancers and AML is one of those. Therefore, the inhibition of estrogen production becomes a potential strategy for AML treatment. Exemestane is an aromatase inhibitor and commonly used for reducing estrogen production in breast cancer patients. Our data showed that Exemestane treatment significantly decreased the proliferation of both KG-1 and HL-60 AML cell lines. Since STAT3 and AKT closely collaborate with estrogen receptor in breast cancer cells, their activations are next to be monitored. In KG-1 cells, the phosphorylations of STAT3 (Y705 and S727) and AKT (S473) were both inhibited by Exemestane treatment. Regarding the cell cycle control, p21 was increased by Exemestane in KG-1 cells in which Cyclin E was reduced. It suggests that CDK2 might be inactivated by Exemestane-reduced Cyclin E and therefore p21 escaped from the CDK2-dependent degradation. Although the signaling findings of Exemestane in KG-1 were interesting, no similar results were found in HL-60 cells except the growth inhibition, suggesting the distinct regulation mechanisms between two cell lines. In summary, these results not only suggest, again, the importance of estrogen demand for AML cells, but also show the novel and potential treatment of AML using blockade of estrogen supply, which could be helpful to uncover novel AML treatments in the future. Citation Format: Mei-chih Chen, Pang-Ting Cheng, Yu-Chiao Cheng, Ho Lin, Chieh-Lin Jerry Teng. Exemestane inhibits survival and cell cycle regulators and retards AML cell proliferation [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A32.
Selected Articles from This Issue
Journal: Clinical Cancer Research (2023)

Biomarkers to define patients unlikely to derive benefit from endocrine therapy combined with CDK4/6 inhibitor are limited.Davis and colleagues performed a comprehensive biomarker analysis from a phase II clinical trial to evaluate whole-exome sequencing and genome-wide copy-number burden using circulating tumor DNA.These studies defined a subset of patients with high tumor mutational burden and elevated copy-number burden with shorter progression-free survival, and these assays offer opportunities as noninvasive tools for baseline tumor assessment and serial disease monitoring.Prospective studies are needed to define novel treatment strategies for patients with genomically complex disease.
Stretchable ultrasonic arrays for the three-dimensional mapping of the modulus of deep tissue
Authors: Hongjie Hu, Yuxiang Ma, Xiaoxiang Gao, Dawei Song, Mohan Li, Hao Huang, Xuejun Qian, Ray Wu, Keren Shi, Hong Ding, Muyang Lin, Xiangjun Chen, Wenbo Zhao, Baiyan Qi, Sai Zhou, Ruimin Chen, Yue Gu, Yimu Chen, Yusheng Lei, Chonghe Wang, Chunfeng Wang, Yitian Tong, Haotian Cui, Abdulhameed Abdal, Yangzhi Zhu, Xinyu Tian, Zhaoxin Chen, Chengchangfeng Lu, Xinyi Yang, Jing Mu, Zhiyuan Lou, Mohammad Eghtedari, Qifa Zhou, Assad Oberai, Sheng Xu
Journal: Nature Biomedical Engineering (2023)

Serial assessment of the biomechanical properties of tissues can be used to aid the early detection and management of pathophysiological conditions, to track the evolution of lesions and to evaluate the progress of rehabilitation. However, current methods are invasive, can be used only for short-term measurements, or have insufficient penetration depth or spatial resolution. Here we describe a stretchable ultrasonic array for performing serial non-invasive elastographic measurements of tissues up to 4 cm beneath the skin at a spatial resolution of 0.5 mm. The array conforms to human skin and acoustically couples with it, allowing for accurate elastographic imaging, which we validated via magnetic resonance elastography. We used the device to map three-dimensional distributions of the Young's modulus of tissues ex vivo, to detect microstructural damage in the muscles of volunteers before the onset of soreness and to monitor the dynamic recovery process of muscle injuries during physiotherapies. The technology may facilitate the diagnosis and treatment of diseases affecting tissue biomechanics.
The immunopeptidome landscape associated with T cell infiltration, inflammation and immune editing in lung cancer
Authors: Anne I. Kraemer, Chloe Chong, Florian Huber, HuiSong Pak, Brian J. Stevenson, Markus Müller, Justine Michaux, Emma Ricart Altimiras, Sylvie Rusakiewicz, Laia Simó-Riudalbas, Evarist Planet, Maciej Wiznerowicz, Julien Dagher, Didier Trono, George Coukos, Stephanie Tissot, Michal Bassani-Sternberg
Journal: Nature Cancer (2023)

Abstract One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. Although patients with CD3 + CD8 + T cell-inflamed tumors typically show better response to immune checkpoint inhibitors, it is still unknown whether the immunopeptidome repertoire presented in highly inflamed and noninflamed tumors is substantially different. We surveyed 61 tumor regions and adjacent nonmalignant lung tissues from 8 patients with lung cancer and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics, and explored the heterogeneous expression and presentation of tumor (neo)antigens. In the present study, we associated diverse immune cell populations with the immunopeptidome and found a relatively higher frequency of predicted neoantigens located within HLA-I presentation hotspots in CD3 + CD8 + T cell-excluded tumors. We associated such neoantigens with immune recognition, supporting their involvement in immune editing. This could have implications for the choice of combination therapies tailored to the patient’s mutanome and immune microenvironment.
Abstract IA09: Epigenomic landscapes of MDS
Authors: Maria E. Figueroa
Journal: Blood Cancer Discovery (2023)

Abstract While significant progress has been made to understand the genetic landscape of MDS, less is known about the epigenetic makeup of this disease and how this may impact biology and response to azacitidine (AZA). To address this, we performed genomic, epigenomic and transcriptomic analysis on CD34+ cells from a multicenter cohort of 94 intermediate or higher risk MDS patients treated with AZA who had documented responses. DNA methylation (DNAme) by ERRBS, gene expression (GE) by RNA-seq, mutational profiling, and detailed clinical, cytogenetic and laboratory data were documented. Supervised and unsupervised analyses revealed that aberrant DNAme in MDS is not distributed randomly but rather is highly correlated with disease phenotypes, capturing clinically relevant heterogeneity, beyond what is identified by methodologies used in the past that focused solely on promoter regions. Moreover, this epigenetic information can be harnessed for the development of robust biomarkers predictive of AZA response and integrative approaches combining GE and DNAme data can further improve the predictive performance of these biomarkers, with an AUC score=0.92. Citation Format: Maria E. Figueroa. Epigenomic landscapes of MDS [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr IA09.
Biobank-scale inference of ancestral recombination graphs enables genealogical analysis of complex traits
Authors: Brian C. Zhang, Arjun Biddanda, Árni Freyr Gunnarsson, Fergus Cooper, Pier Francesco Palamara
Journal: Nature Genetics (2023)

Abstract Genome-wide genealogies compactly represent the evolutionary history of a set of genomes and inferring them from genetic data has the potential to facilitate a wide range of analyses. We introduce a method, ARG-Needle, for accurately inferring biobank-scale genealogies from sequencing or genotyping array data, as well as strategies to utilize genealogies to perform association and other complex trait analyses. We use these methods to build genome-wide genealogies using genotyping data for 337,464 UK Biobank individuals and test for association across seven complex traits. Genealogy-based association detects more rare and ultra-rare signals ( N = 134, frequency range 0.0007−0.1%) than genotype imputation using ~65,000 sequenced haplotypes ( N = 64). In a subset of 138,039 exome sequencing samples, these associations strongly tag (average r = 0.72) underlying sequencing variants enriched (4.8×) for loss-of-function variation. These results demonstrate that inferred genome-wide genealogies may be leveraged in the analysis of complex traits, complementing approaches that require the availability of large, population-specific sequencing panels.
Spatial transcriptomic analysis of Sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition
Authors: Tuan Vo, Brad Balderson, Kahli Jones, Guiyan Ni, Joanna Crawford, Amanda Millar, Elissa Tolson, Matthew Singleton, Marija Kojic, Thomas Robertson, Shaun Walters, Onkar Mulay, Dharmesh D. Bhuva, Melissa J. Davis, Brandon J. Wainwright, Quan Nguyen, Laura A. Genovesi
Journal: Genome Medicine (2023)

Abstract Background Medulloblastoma (MB) is a malignant tumour of the cerebellum which can be classified into four major subgroups based on gene expression and genomic features. Single-cell transcriptome studies have defined the cellular states underlying each MB subgroup; however, the spatial organisation of these diverse cell states and how this impacts response to therapy remains to be determined. Methods Here, we used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of MB and show that cells specific to a transcriptional state or spatial location are pivotal for CDK4/6 inhibitor, Palbociclib, treatment response. We integrated spatial gene expression with histological annotation and single-cell gene expression data from MB, developing an analysis strategy to spatially map cell type responses within the hybrid system of human and mouse cells and their interface within an intact brain tumour section. Results We distinguish neoplastic and non-neoplastic cells within tumours and from the surrounding cerebellar tissue, further refining pathological annotation. We identify a regional response to Palbociclib, with reduced proliferation and induced neuronal differentiation in both treated tumours. Additionally, we resolve at a cellular resolution a distinct tumour interface where the tumour contacts neighbouring mouse brain tissue consisting of abundant astrocytes and microglia and continues to proliferate despite Palbociclib treatment. Conclusions Our data highlight the power of using spatial transcriptomics to characterise the response of a tumour to a targeted therapy and provide further insights into the molecular and cellular basis underlying the response and resistance to CDK4/6 inhibitors in SHH MB.
Suppression of local inflammation via galectin-anchored indoleamine 2,3-dioxygenase
Authors: Evelyn Bracho-Sanchez, Fernanda G. Rocha, Sean K. Bedingfield, Brittany D. Partain, Sabrina L. Macias, Maigan A. Brusko, Juan M. Colazo, Margaret M. Fettis, Shaheen A. Farhadi, Eric Y. Helm, Kevin Koenders, Alexander J. Kwiatkowski, Antonietta Restuccia, Bethsymarie Soto Morales, Arun Wanchoo, Dorina Avram, Kyle D. Allen, Craig L. Duvall, Shannon M. Wallet, Gregory A. Hudalla, Benjamin G. Keselowsky
Journal: Nature Biomedical Engineering (2023)

The treatment of chronic inflammation with systemically administered anti-inflammatory treatments is associated with moderate-to-severe side effects, and the efficacy of locally administered drugs is short-lived. Here we show that inflammation can be locally suppressed by a fusion protein of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO) and galectin-3 (Gal3). Gal3 anchors IDO to tissue, limiting the diffusion of IDO-Gal3 away from the injection site. In rodent models of endotoxin-induced inflammation, psoriasis, periodontal disease and osteoarthritis, the fusion protein remained in the inflamed tissues and joints for about 1 week after injection, and the amelioration of local inflammation, disease progression and inflammatory pain in the animals were concomitant with homoeostatic preservation of the tissues and with the absence of global immune suppression. IDO-Gal3 may serve as an immunomodulatory enzyme for the control of focal inflammation in other inflammatory conditions.
Nomenclature and diagnosis of seronegative celiac disease and chronic non-celiac enteropathies in adults
Authors: O.Yu. Gubska, O.R. Denesyuk
Journal: GASTROENTEROLOGY (2023)

Small bowel villous atrophy is one of the main histopathological manifestations of chronic enteropathy. In most cases, this condition is caused by celiac disease. Celiac disease is an autoimmune disease that occurs in genetically predisposed individuals and is characterized by damage to the mucous membrane of the small intestine (T-cell-mediated enteropathy) due to the influence of gluten and is treated with the help of a lifelong gluten-free diet. Diagnosis of classic celiac disease does not cause difficulties. Diagnostic algorithms have been developed for years. Diagnostic problems arise when small bowel villous atrophy occurs in patients who have gastrointestinal symptoms but are negative for celiac disease-specific antibodies. Differential diagnosis of small bowel villous atrophy without serological markers for celiac disease in adults includes seronegative celiac disease and chronic non-celiac enteropathies. There has long been diagnostic and clinical uncertainty about these conditions. This uncertainty has led to misdiagnoses and increased the number of people following a gluten-free diet unnecessarily. Between September 2019 and July 2021, an international working group of 13 gastroenterologists from six countries worked to create a consensus on the nomenclature and diagnosis of seronegative celiac disease and non-celiac enteropathies in adults.
Esau brothers: Yakiv, a doctor, and Ivan, a head of the town
Authors: M.P. Chaban, Z.I. Shevtsova, V.V. Gaponov
Journal: GASTROENTEROLOGY (2023)

The article highlights the thorny life and professional path of the German Mennonites brothers Esau. Yakiv became a doctor, and his brother Ivan became the head of Katerynoslav. Their contribution to the development of medicine and industry in the Dnieper region has been represented. The fate of their descendants has been found out.